Metformin Enhances the Effect of Regorafenib and Inhibits Recurrence and Metastasis of Hepatic Carcinoma After Liver Resection via Regulating Expression of Hypoxia Inducible Factors 2α (HIF-2α) and 30 kDa HIV Tat-Interacting Protein (TIP30)

Despite sorafenib effectiveness against advanced hepatocarcinoma (HCC), long-term exposure to antiangiogenic drugs leads to hypoxic microenvironment, a key contributor to chemoresistance acquisition. We aimed to study the role of hypoxia in the development of sorafenib resistance in a human HCC in vitro model employing the HCC line HepG2 and two variants with acquired sorafenib resistance, HepG2S1 and HepG2S3, and CoCl2 as hypoximimetic. Resistant cells exhibited a faster proliferative rate and hypoxia adaptive mechanisms, linked to the increased protein levels and nuclear translocation of hypoxia-inducible factors (HIFs). HIF-1α and HIF-2α overexpression was detected even under normoxia through a deregulation of its degradation mechanisms. Proapoptotic markers expression and subG1 population decreased significantly in HepG2S1 and HepG2S3, suggesting evasion of sorafenib-mediated cell death. HIF-1α and HIF-2α knockdown diminished resistant cells viability, relating HIFs overexpression with its prosurvival ability. Additionally, epigenetic silencing of Bcl-2 interacting protein 3 (BNIP3) was observed in sorafenib resistant cells under hypoxia. Demethylation of BNIP3 promoter, but not histone acetylation, restored BNIP3 expression, driving resistant cells’ death. Altogether, our results highlight the involvement of HIFs overexpression and BNIP3 methylation-dependent knockdown in the development of sorafenib resistance in HCC. Targeting both prosurvival mechanisms could overcome chemoresistance and improve future therapeutic approaches.

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Finding a novel interacting protein of the hepatic carcinoma related gene MIP: NF-κB essential modulator (NEMO)

Oncology Reports ◽

10.3892/or_00001065 ◽

2010 ◽

Vol 25 (1) ◽

Author(s):

Ye

Keyword(s):

Related Gene ◽

Hepatic Carcinoma ◽

Interacting Protein

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Early signalling events of autophagy

Essays in Biochemistry ◽

10.1042/bse0550001 ◽

2013 ◽

Vol 55 ◽

pp. 1-15 ◽

Cited By ~ 16

Author(s):

Laura E. Gallagher ◽

Edmond Y.W. Chan

Keyword(s):

Protein Kinase ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Mammalian Cells ◽

Mammalian Target Of Rapamycin ◽

Interacting Protein ◽

The Core ◽

Autophagy Gene ◽

Autophagy Induction ◽

Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

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Functional amyloid: widespread in Nature, diverse in purpose

Essays in Biochemistry ◽

10.1042/bse0560207 ◽

2014 ◽

Vol 56 ◽

pp. 207-219 ◽

Cited By ~ 77

Author(s):

Chi L.L. Pham ◽

Ann H. Kwan ◽

Margaret Sunde

Keyword(s):

Spider Silk ◽

Epigenetic Inheritance ◽

Fibrillar Structure ◽

Cytoplasmic Polyadenylation ◽

Functional Amyloid ◽

Interacting Protein ◽

Diverse Range ◽

Element Binding Protein ◽

Functional Amyloids ◽

Micro Organisms

Amyloids are insoluble fibrillar protein deposits with an underlying cross-β structure initially discovered in the context of human diseases. However, it is now clear that the same fibrillar structure is used by many organisms, from bacteria to humans, in order to achieve a diverse range of biological functions. These functions include structure and protection (e.g. curli and chorion proteins, and insect and spider silk proteins), aiding interface transitions and cell–cell recognition (e.g. chaplins, rodlins and hydrophobins), protein control and storage (e.g. Microcin E492, modulins and PMEL), and epigenetic inheritance and memory [e.g. Sup35, Ure2p, HET-s and CPEB (cytoplasmic polyadenylation element-binding protein)]. As more examples of functional amyloid come to light, the list of roles associated with functional amyloids has continued to expand. More recently, amyloids have also been implicated in signal transduction [e.g. RIP1/RIP3 (receptor-interacting protein)] and perhaps in host defence [e.g. aDrs (anionic dermaseptin) peptide]. The present chapter discusses in detail functional amyloids that are used in Nature by micro-organisms, non-mammalian animals and mammals, including the biological roles that they play, their molecular composition and how they assemble, as well as the coping strategies that organisms have evolved to avoid the potential toxicity of functional amyloid.

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Liver Resection for Liver Metastasis - the Bernese Results

Swiss Surgery ◽

10.1024/1023-9332.6.4.164 ◽

2000 ◽

Vol 6 (4) ◽

pp. 164-168 ◽

Cited By ~ 3

Author(s):

Seiler ◽

Redaelli ◽

Schmied ◽

Baer ◽

Büchler

Keyword(s):

Liver Resection ◽

Liver Metastasis ◽

Chirurgische Resektion ◽

Kurative Therapie

Neue Erkenntnisse über die Anatomie und Funktion der Leber haben dazu geführt, dass heute die chirurgische Resektion die Therapie der Wahl bei Lebermetastasen geworden ist. Obschon Lebermetastasen ein fortgeschrittenes Tumorstadium bedeuten, werden infolge besserer Kenntnisse der Karzinogenese (Mikrometastasen etc.) sowie der prognostischen Risikofaktoren erwiesenermassen die besten Langzeitresultate durch die chirurgische Resektion erzielt. In dieser Studie wurden die Ergebnisse von 109 Resektionen von kolorektalen sowie nicht kolorektalen Lebermetastasen an unserer Klinik während eines Zeitraumes von 59 Monaten zusammengefasst. Vier verschiedene Operationsverfahren (formelle Hemihepatektomie vs Segmentresektion vs atypische Resektion vs Biopsie) wurden untersucht. Die Einhaltung eines Resektionsabstandes von mindestens 10 mm wurde bei Resektionen immer angestrebt. Die kumulierte Morbidität aller Operationsverfahren zusammen betrug 23%. Obwohl die Morbidität bei ausgedehnten Resektionen höher war (Encephalopathie 16% vs 2.3% bei der Segmentresektion, Leberinsuffizienz 23% vs 4.7%), war das Langzeitüberleben gegenüber den limitierten Resektionsverfahren verbessert. Die 60-Tage Mortalität lag bei 2.7%. Patienten nach Resektion von kolorektalen Lebermetastasen hatten eine höhere Ueberlebensrate als diejenigen nach Resektion nicht kolorektaler Metastasen. Unsere Resultate zeigen, dass die Leberresektion heutzutage unter Einhaltung der anatomischen sowie funktionellen Grenzen (inkl. eines adäquaten Resektionsrandes) die einzige, potentiell kurative Therapie von Lebermetastasen darstellt. Trotz erhöhter perioperativer Morbidität ist die ausgedehnte formelle Resektion den limitierten Operationsverfahren bezüglich Langzeitüberleben überlegen. Ein Grund dafür ist die erhöhte Wahrscheinlichkeit einer Mitresektion von präoperativ nicht detektierbaren lokalen Mikrometastasen.

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AH Receptor-Interacting Protein

10.32388/niwhnd ◽

2020 ◽

Author(s):

Keyword(s):

Ah Receptor ◽

Interacting Protein

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PC4 and SFRS1-Interacting Protein Isoform 2

10.32388/q75v9f ◽

2020 ◽

Author(s):

Keyword(s):

Interacting Protein ◽

Protein Isoform

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Radiofrequency ablation of colorectal liver metastases

Perspectives in Surgery ◽

10.33699/pis.2019.98.10.399-403 ◽

2019 ◽

Vol 98 (10) ◽

Keyword(s):

Radiofrequency Ablation ◽

Liver Resection ◽

Liver Metastases ◽

Colorectal Liver Metastases ◽

Survival Rates ◽

Postoperative Mortality ◽

Disease Free Survival ◽

Female Ratio ◽

Liver Resections ◽

Multi Stage

Introduction: Radical liver resection is the only method for the treatment of patients with colorectal liver metastases (CLM); however, only 20–30% of patients with CLMs can be radically treated. Radiofrequency ablation (RFA) is one of the possible methods of palliative treatment in such patients. Methods: RFA was performed in 381 patients with CLMs between 01 Jan 2001 and 31 Dec 2018. The mean age of the patients was 65.2±8.7 years. The male to female ratio was 2:1. Open laparotomy was done in 238 (62.5%) patients and the CT-navigated transcutaneous approach was used in 143 (37.5%) patients. CLMs <5 cm (usually <3 cm) in diameter were the indication for RFA. We used RFA as the only method in 334 (87.6%) patients; RFA in combination with resection was used in 36 (9.4%), and with multi-stage resection in 11 (3%) patients. We performed RFA in a solitary CLM in 170 (44.6%) patients, and in 2−5 CLMs in 211 (55.6%) patients. We performed computed tomography in each patient 48 hours after procedure. Results: The 30-day postoperative mortality was zero. Complications were present in 4.8% of transcutaneous and in 14.2% of open procedures, respectively, in the 30-day postoperative period. One-, 3-, 5- and 10-year overall survival rates were 94.8, 66.8, 43.9 and 16.6%, respectively, in patients undergoing RFA, and 90.6, 69.1, 52.8 and 39.2%, respectively, in patients with liver resections. Disease free survival was 63.2, 30.1, 18.4 and 13.1%, respectively, in the same patients after RFA, and 71.1, 33.3, 22.8 and 15.5%, respectively, after liver resections. Conclusion: RFA is a palliative thermal ablation method, which is one of therapeutic options in patients with radically non-resectable CLMs. RFA is useful especially in a non-resectable, or resectable (but for the price of large liver resection) solitary CLM <3 cm in diameter and in CLM relapses. RFA is also part of multi-stage liver procedures.

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